Reductive alkylation process for the preparation of compounds containing at least two amino groups

ABSTRACT

An alkylation process is described. The process comprises reacting at least a first nitrogen compound and a second nitrogen compound with a carbonyl compound in the presence of a reducing agent to form a product comprising at least two nitrogen groups; wherein the carbonyl compound comprises at least two carbonyl groups, the first nitrogen compound comprises a first nitrogen group reactive with one carbonyl group of the carbonyl compound and the second nitrogen compound comprises a second nitrogen group reactive with the other (or another) carbonyl group of the carbonyl compound, and wherein at least the first nitrogen compound or at least the second nitrogen compound comprises at least one other functional group. The process is especially suitable for the preparation of (S,S)-ethylenediaminedisuccinic acid (EDDS) of formula (1).

The present invention relates to an alkylation process. In particular,the present invention relates to a process for alkylating amino acids.

More in particular, the present invention relates to a process for theN-alkylation of amino acids, and especially a process for preparing(S,S)-ethylenediaminedisuccinic acid or a salt thereof.

Certain compounds having amino acid moieties linked by a group joiningtheir nitrogen atoms have a variety of uses mainly based on their metalchelating properties. Typical examples include their use as corrosioninhibitors, and in detergents, photographic developing solutions, rubberand resin formulations and metal treatments. One particular example isethylenediaminedisuccinic acid (“EDDS”) which has two chiral centres.The S,S-enantiomer of EDDS is preferred because of its biodegradabilityand its better chelating properties. EDDS is shown in FIG. 1.

Racemic EDDS is usually prepared by the reaction of maleic anhydridewith ethylenediamine in NaOH solution, according to the procedure by W.M. Ramsey and C. Kerzerian of the Stauffer Chemical Company, U.S. Pat.No. 3,158,635. (S,S)-EDDS can be manufactured by a variety of differentroutes. A typical route is the reaction of NaOH with L-aspartic acid anddibromoethane following the protocol of Neal, J. A. and Rose, N. J.(Inorganic Chemistry, Vol. 7, No. 11, November 1968, pages 2405-2412,particularly page 2406). However, even though this synthetic route isthe one that is typically used it is usually difficult to obtaineconomic yields of (S,S)-EDDS. Furthermore it is difficult to obtainhighly pure (S,S)-EDDS.

The present invention seeks to overcome the problems associated with theknown processes. In particular, the present invention seeks to provide aprocess that enables compounds like EDDS, more especially (S,S)-EDDS, tobe prepared in high yields, economic yields and/or high purity.

According to the present invention there is provided an alkylationprocess comprising reacting at least a first nitrogen compound and asecond nitrogen compound with a carbonyl compound in the presence of areducing agent to form a product comprising at least two nitrogengroups; wherein the carbonyl compound comprises at least two carbonylgroups, the first nitrogen compound comprises a first nitrogen groupreactive with one carbonyl group of the carbonyl compound and the secondnitrogen compound comprises a second nitrogen group reactive with theother (or another) carbonyl group of the carbonyl compound, and whereinat least the first nitrogen compound or at least the second nitrogencompound comprises at least one other functional group.

There are a number of advantages associated with the present invention.For example, it enables compounds like EDDS, more especially (S,S)-EDDS,to be prepared in high yields. It also enables compounds like EDDS, moreespecially (S,S)-EDDS, to be prepared in economic yields. It alsoenables compounds like EDDS, more especially (S,S)-EDDS, to be preparedat a high purity. The present invention also provides a reliable processfor preparing optically active compounds, such as (S,S)-EDDS, by use ofa substantially aqueous reaction medium/media. Furthermore, the presentinvention provides a process that allows reduction in situ withoutrequiring the need to isolate any intermediates in the reaction process.In some cases the intermediate or intermediates could be isolated, butpreferably the intermediate or intermediates is/are not isolated.

In the process of the present invention the first nitrogen compoundand/or the second nitrogen compound can comprise more than oneadditional nitrogen group, which need not be reactive with the carbonylgroups of the carbonyl compound. Also, in the process of the presentinvention an additional nitrogen compound or additional nitrogencompounds may be reacted. Also, an additional carbonyl compound oradditional carbonyl compounds may be reacted, which carbonyl compound orcarbonyl compounds can independently comprise one or more carbonylgroups. Also, a mixture of reducing agents may be used in the process ofthe present invention. In addition, at least the first nitrogen compoundand/or at least the second nitrogen compound can comprise an additionalfunctional group or additional functional groups. Other reactivecompounds may be present in the reaction medium.

Preferably the first nitrogen group and the second nitrogen group areindependently selected from a primary amine group or a secondary aminegroup.

Preferably each of the first nitrogen group and the second nitrogengroup is a primary amine group, which may be the same or different.

Preferably the functional group is an acid group.

Preferably the acid group is a carboxylic acid group.

Preferably at least the first nitrogen compound or at least the secondnitrogen compound comprises at least one chiral centre. More preferablyat least the first nitrogen compound and at least the second nitrogencompound comprises at least one chiral centre.

Preferably the first nitrogen compound or the second nitrogen compoundcomprises 1-20 carbon atoms, more preferably 1-12 carbon atoms.

Preferably the first nitrogen compound or the second nitrogen compoundis an amino acid.

Typical amino acids for use in the process of the present inventioninclude any one or more of the 26 or so naturally occurring amino acidslisted in standard textbooks, including the derivatives thereof. Theamino acid may be any one or more of a “neutral” amino acid, a “basic”amino acid or an “acidic” amino acid. However, preferably the amino acidfor use in the process of the present invention is not cysteine. This isbecause this amino acid has an -SH group which could undergo unwantedside reactions.

In the process of the present invention an amino acid having an α-aminogroup (e.g. aspartic acid) can be reacted. Alternatively, or inaddition, in the process of the present invention an amino acid having aβ-amino group (e.g. β-alanine) can be reacted.

Examples of neutral amino acids that may be used in the presentinvention include glycine, alanine, valine, leucine, norleucine,phenylalanine, tyrosine, serine, cystine, threonine, methionine,di-iodotyrosine, thyroxine, dibromotyrosine, tryptophan, proline andhydroxyproline.

Examples of basic amino acids that may be used in the present inventioninclude ornithine, arginine, lysine and histidine.

Examples of acidic amino acids that may be used in the process of thepresent invention include aspartic acid, glutamic acid andβ-hydroxyglutainic acid.

The preferred amino acids for the process of the present invention arethose with two carboxyl groups and one amino group—i.e. the acidic aminoacids listed above. Aspartic acid and glutamic acid are the mostpreferred of the three.

Specific optical isomers, particularly the L-form, are desirable becausethey increase biodegradability and in some cases, may also improve thechelating effect.

Preferably, therefore, the first nitrogen compound or the secondnitrogen compound is an acidic amino acid.

Preferably the first nitrogen compound or the second nitrogen compoundis aspartic acid.

Preferably the first nitrogen compound or the second nitrogen compoundis an L-amino acid.

Preferably the first nitrogen compound or the second nitrogen compoundis L-aspartic acid.

Alternatively, other amino acids may be reacted in the process of thepresent invention, such as D- or DL- amino acids, for example D-asparticacid or DL-aspartic acid, to generate corresponding R,R- or racemicproducts having at least two nitrogen groups, such as R,R- or racemicEDDS.

Preferably the first nitrogen compound is the same as the secondnitrogen compound.

Preferably at least one of the carbonyl groups of the carbonyl compoundis an aldehyde group or a ketone group.

Preferably at least one of the carbonyl groups of the carbonyl compoundis an aldehyde group or a ketone group, and wherein at least one otherof the carbonyl groups of the carbonyl compound is an aldehyde group ora ketone group.

Preferably at least one carbonyl group is an aldehyde group.

Preferably the carbonyl compound comprises two carbonyl groups—i.e. thecarbonyl compound is a di-carbonyl compound.

Preferably the carbonyl groups of the carbonyl compound are the same.

Preferably the carbonyl compound is a di-aldehyde.

Preferably the carbonyl groups of the carbonyl compound are attached toeach other or to groups independently selected from any one of saturatedor unsaturated, linear or branched or cyclic aliphatic groups(preferably C₁₋₂₀, more preferably C₁₋₁₂) or aromatic groups (preferablyC₁₋₂₀, more preferably C₁₋₁₂). More preferably the at least two carbonylgroups of the carbonyl compound are attached to each other.

Preferably the carbonyl compound is glyoxal.

Preferably the reducing agent is any one of hydrogen and a hydrogenationcatalyst, Zn/HCl, sodium cyanoborohydride, sodium borohydride, ironpentacarbonyl and alcoholic KOH, or formic acid, or combinationsthereof.

The process of the present invention can be conducted at any appropriatepH condition.

Preferably, though, the process is conducted at a pH in the range of7-14, more preferably in the range of 9-14 and even more preferably inthe range 11-14. The pH may be maintained with alkali (i.e. a base),typically aq. NaOH solution, though a wide variety of water-solubleinorganic and organic bases may be used. In some instances, it will bedesirable to add alkali during the reaction.

The reaction medium is normally wholly aqueous but the presence of othersolvents such as ethanol is not excluded. In some circumstances, alkali(base) may be provided wholly or in part by other components of thereaction medium, particularly when the first nitrogen compound and/orthe second nitrogen compound is(are) in salt form.

Typically the alkylated product will be generally less soluble than thestarting reactants so that the reaction mixture can be diluted to alevel at which remaining starting reactant or reactants is(are) soluble,followed by acidification and selective crystallisation of the desiredproduct.

Preferably, therefore, the first nitrogen compound and the secondnitrogen compound are reacted with the carbonyl compound in an alkalinemedium.

Preferably the first nitrogen compound and the second nitrogen compoundare reacted with the carbonyl compound before addition of the reducingagent.

Preferably the product comprising at least two nitrogen groups containsat least one chiral centre, preferably at least two chiral centres.

Preferably the carbonyl compound is prepared in situ in the reactionmedium.

Preferably the product comprising at least two nitrogen groups is EDDS.

Preferably the product comprising at least two nitrogen groups is(S,S)-EDDS.

The product comprising at least two nitrogen groups may be prepared insalt form by the process of the present invention. Typically, thoughmore preferred for the preparation of (S,S)-EDDS via the reaction ofL-aspartic acid with glyoxal and subsequent reduction, the reactionsolution of the present invention is preferably acidified with HCl to apH of between 2 and 5, preferably 2-3 with cooling, for the desiredproduct to crystallise out.

The following table presents some preferred parameters for the presentinvention.

Parameters General Range Preferred Range Ratio of N1 + N2:CC:RA1:0.5-8:0.5-4 1:0.8-2:0.8-2 pH 6-14 11-14 Reaction temperature −5 to 65°C. 5 to 40° C. Reaction time Up to 18 hrs 10 min-3 hrs Temperature of RAaddition −5 to 60° C. 0 to 40° C. Time of RA addition 5 min-8 hrs 15min-4 hrs [N1 + N2 = first nitrogen containing compound plus secondnitrogen containing compound; CC = carbonyl compound; RA = reducingagent.]

A preferred embodiment of the present invention relates to an alkylationprocess comprising reacting at least a first amino acid and a secondamino acid with a carbonyl compound in the presence of a reducing agentto form a product comprising at least two nitrogen groups; wherein thecarbonyl compound comprises at least two carbonyl groups.

With this preferred embodiment, the process of the present invention mayinclude the reaction of an aldehyde or a ketone with an amine as definedin the claims in the presence of hydrogen and a hydrogenation catalyst,whereby reductive alkylation of ammonia or the amine (or reductiveamination of the carbonyl compound) takes place. Other reducing agentscan be used instead of hydrogen and a catalyst, such as Zn/HCl, sodiumcyanoborohydride, sodium borohydride, iron pentacarbonyl and alcoholicKOH, and formic acid.

A highly preferred embodiment of the present invention relates to analkylation process comprising reacting L-aspartic acid with glyoxal inthe presence of a reducing agent to form (S,S)-EDDS.

Thus, with this highly preferred embodiment, the process of the presentinvention involves the reductive N-alkylation of amino acids withglyoxal (a dialdehyde) to form a derivative which contains two moleculesof the amino acid, linked together through the two nitrogen atoms by anethyl chain.

More specifically, the highly preferred process of the present inventioninvolves reacting L-aspartic acid in aqueous alkaline media withglyoxal, a dialdehyde, to form the corresponding intermediate, which issubsequently reduced with sodium borohydride. From an economicviewpoint, unreacted L-aspartic acid can be recycled. The use ofalternate reducing agents such as hydrogen/catalyst is more economicallyviable. The preferred order of addition is that of the glyoxal to thesodium L-aspartate, followed by the addition of the sodium borohydride.Further glyoxal and sodium borohydride may be added as required.

As mentioned above, the carbonyl compound can be prepared in situ in thereaction medium. In this regard, a primary alcohol may be oxidised tothe corresponding aldehyde by use of a reduced copper catalyst. Theprimary alcohol could even be subjected to the catalysed reduction inthe presence of an amine. The resultant aldehyde can then be reactedwith an amine to form an N-alkylamine by hydrogenolysis (such as in situhydrogenolysis) of the intermediate. These postulated reaction schemesare presented below:

RCH₂OH → RCHO + H₂ RNH₂ + RCHO → RNHCH(OH)R RNHCH(OH)R + H₂ → RNHCH₂R +H₂O

wherein R represents a suitable alkyl (which may be any one ofsaturated, unsaturated, unsubstituted, substituted, linear or branched)or aryl group (unsubstituted or substituted).

For the process of the present invention, the primary alcohol could beethylene glycol which could be oxidised to glyoxal with the reducedcopper catalyst. Further reaction with L-aspartic acid produces(S,S)-EDDS under the hydrogenolysis conditions.

The present invention will now be described only by way of example, inwhich reference shall be made to the following Figures:

FIG. 1 is a representation of EDDS; and

FIG. 2 is a schematic representation of the preparation of EDDS by theprocess according to the present invention.

In the following examples, the term “conversion” refers to the weight ofamino acid (i.e. the nitrogen compound) reacted (to form any product)divided by the weight of amino acid present initially ×100%. The term“selectivity” refers to the weight of amino acid reacted to form thedesired product divided by the total amount of amino acid reacted ×100%.

EXAMPLE 1

L-Aspartic acid (5.26 g, 39.5 mmoles) was placed in a reaction flask,followed by distilled water (50 ml). The pH was adjusted to 11.6 withsodium hydroxide solution (6.31 g, 78.8 mmoles, 50% w/w) and glyoxal(5.71 g, 39.4 mmoles, 40 wt % solution in water) was added. After 15minutes, the solution was cooled (ice/water bath) and sodium borohydride(1.69 g, 44.7 mmoles) was added portion-wise over 1.5 hours.

HPLC analysis after this time indicated a yield of 49% (2.81 g)(S,S)-ethylenediaminedisuccinic acid on L-aspartic acid.

Acidification of the solution to pH 2.7 with HCl resulted in theformation of solids. After 1 hour, the slurry was filtered and thesolids were washed with water.

The mother liquors and washings were combined and the cake was slurriedin water and basified to pH 9.5. HPLC analysis indicated that the motherliquors and washings contained 2.32 g L-asp and 0.14 g (S,S)-EDDS, andthe cake contained 0.07 g L-asp and 2.6 g (S,S)-EDDS. This relates to anisolated yield of (S,S)-EDDS of 45%. The conversion of L-aspartic acidwas 54.5% and the selectivity to (S,S)-EDDS was 87%. The generalreaction scheme is shown in FIG. 2.

EXAMPLE 2

L-Aspartic acid (5.39 g, 40.5 mmoles) was placed in a reaction flask,followed by distilled water (50 ml). The pH was adjusted to 13.53 withsodium hydroxide solution (50% w/w) and glyoxal (5.89 g, 40.6 mmoles, 40wt % solution in water) was added. After 15 minutes, the solution wascooled (ice/water bath) and sodium borohydride (1.74 g, 46 mmoles) wasadded portion-wise over 2 hours.

HPLC analysis after this time indicated a yield of 56%(S,S)-ethylenediaminedisuccinic acid on L-aspartic acid. Acidificationwith HCl to pH 2.6 afforded an isolated yield of 52% (S,S)-EDDS. Theconversion of L-aspartic acid was 63% and the selectivity to (S,S)-EDDSwas 90%. The general reaction scheme is shown in FIG. 2.

EXAMPLE 3

L-Aspartic acid (5.26 g, 39.5 mmoles) was placed in a reaction flask,followed by distilled water (50 ml). The pH was adjusted to 13.5 withsodium hydroxide solution (7.71 g, 96.4 mmoles, 50% w/w) and glyoxal(5.71 g, 39.4 mmoles, 40 wt % solution in water) was added. After 1hour, the solution was cooled to 0° C. (ice/water bath) and sodiumborohydride (1.68 g, 44.4 mmoles) was added portion-wise over 15minutes. The temperature rose to 12° C. HPLC analysis after this timeindicated a yield of 58.4% (3.37 g) (S,S)-ethylenediaminedisuccinic acidon L-aspartic acid. The conversion of L-aspartic acid was 70.5% and theselectivity to (S,S)-EDDS was 83%. The general reaction scheme is shownin FIG. 2.

EXAMPLE 4

The following table presents some preferred parameters for one aspect ofthe highly preferred embodiment of the present invention.

Parameters General Range Preferred Range Ratio of L-asp:glyoxal:NaBH₄1:0.5-8:0.5-4 1:0.8-2:0.8-2 pH 6-14 11-14 Reaction temperature −5 to 65°C. 5 to 40° C. Reaction time Up to 18 hrs 10 min-3 hrs Temperature ofNaBH₄ addition −5 to 60° C. 0 to 40° C. Time of NaBH₄ addition 5 min-8hrs 15 min-4 hrs

In summation, the present invention provides a novel and inventiveprocess for preparing compounds such as EDDS, more especially(S,S)-EDDS. The process of the present invention is very different fromthe known reactions of glyoxal with an amino acid which have beendescribed in gel formation reactions and to produce ‘browning’ in thefood industry. The process of the present invention is very differentfrom the known decarboxylation of an α-amino acid with glyoxal (i.e.Strecker degradation).

Other modifications of the present invention will be apparent to thoseskilled in the art.

What is claimed is:
 1. An alkylation process comprising reacting atleast a first nitrogen compound and a second nitrogen compound with acarbonyl compound in the presence of a reducing agent to form a productcomprising at least two nitrogen groups; wherein said product is EDDS,the carbonyl compound is glyoxal, the first nitrogen compound isaspartic acid and the second nitrogen compound is aspartic acid.
 2. Aprocess according to claim 1 wherein said first nitrogen compound orsaid second nitrogen compound is L-aspartic acid.
 3. A process accordingto claim 1 wherein said first nitrogen compound and said second nitrogencompound are reacted with said carbonyl compound in an alkaline medium.4. A process according to claim 1 wherein said carbonyl compound isprepared in situ in said reaction medium.
 5. An alkylation processcomprising reacting at least a first nitrogen compound and a secondnitrogen compound with a carbonyl compound in the presence of a reducingagent to form a product comprising at least two nitrogen groups; whereinsaid product is (S,S)-EDDS; the carbonyl compound is glyoxal, the firstnitrogen compound is L-aspartic acid and the second nitrogen compound isL-aspartic acid.
 6. A process according to claim 1 wherein the reactionmedium is wholly aqueous.
 7. A process according to claim 1 wherein thereducing agent is a member of the group consisting of hydrogen and ahydrogenation catalyst, Zn/HCl, sodium cyanoborohydride, sodiumborohydride, iron pentacarbonyl and alcoholic KOH, formic acid, and anycombinations of these reducing agents.
 8. A process according to claim 1wherein said first nitrogen compound and said second nitrogen compoundare reacted with said carbonyl compound before addition of the reducingagent.